Nearly all life forms require iron as a micronutrient (Mladenka et al., Acta Medica. 2005, 48, 127-135). However, the low solubility of Fe(III) hydroxide (Ksp=1×10−39) (Raymond et al., “Coordination Chemistry and Microbial Iron Transport.” Acc. Chem. Res. 1979, 12, 183-190), the predominant form of the metal in the biosphere, required the development of sophisticated iron storage and transport systems in nature. Microorganisms utilize low molecular weight, ferric iron-specific chelators, siderophores (Byers et al., “Microbial Iron Transport: Iron Acquisition by Pathogenic Microorganisms.” Met. Ions Biol. Syst. 1998, 35, 37-66); eukaryotes tend to employ proteins to transport and store iron (Gkouvatsos et al., Biochim. Biophys. Acta. 2012, 1820, (2012) 188-202; Li et al., Proc. Natl. Acad. Sci. U.S.A. 107 (2010, 107) 3505-3510; Bergeron, “Iron: A Controlling Micronutrient in Proliferative Processes.” Trends Biochem. Sci. 1986, 11, 133-136; Theil et al., “Ferritin Mineralization: Ferroxidation and Beyond.” J. Inorg. Biochem. 1997, 67, 30; Ponka et al., “Function and Regulation of Transferrin and Ferritin.” Semin. Hematol. 1998, 35, 35-54). Humans have evolved a highly efficient iron management system (Andrews et al., Annu. Rev. Physiol. 69 (2007) 69-85) in which we absorb and excrete only about 1 mg of the metal daily; there is no mechanism for the excretion of excess metal (Whittington et al., Review article: haemochromatosis, Aliment Pharmacol. Ther. 16 (2002) 1963-1975; Brittenham, “Disorders of Iron Metabolism: Iron Deficiency and Overload.” In Hematology: Basic Principles and Practice; 3rd ed.; Hoffman et al., Eds.; Churchill Livingstone: New York, 2000; pp. 397-428). Whether derived from transfused red blood cells (Peters et al., B. M. J. (2012) 344:e228. doi: 10.1136/bmj.e228; Cappellini et al., Guidelines for the Clinical Management of Thalassemia, 2nd Ed., Thalassemia International Foundation, 2008; Olivieri et al., “Iron-Chelating Therapy and the Treatment of Thalassemia.” Blood 1997, 89, 739-761; Vichinsky, “Current Issues with Blood Transfusions in Sickle Cell Disease.” Semin. Hematol. 2001, 38, 14-22; Kersten et al., “Long-Term Treatment of Transfusional Iron Overload with the Oral Iron Chelator Deferiprone (L1): A Dutch Multicenter Trial.” Ann. Hematol. 1996, 73, 247-252), required in the treatment of hemolytic anemias, or from increased absorption of dietary iron (Conrad et al., “Iron Absorption and Transport.” Am. J. Med. Sci. 1999, 318, 213-229; Lieu et al., “The Roles of Iron in Health and Disease.” Mol. Aspects Med. 2001, 22, 1-87), without effective treatment, body iron progressively increases with deposition in the liver, heart, pancreas, and elsewhere (iron overload disease) (Lieu et al., Mol. Aspects Med. 22 (2001) 1-87). This can lead to liver disease (Bonkovsky et al., Clin. Liver Dis. 4 (2000) 409-429, vi-vii), diabetes (Wojcik et al., Can. J. Gastroenterol. 16 (2002) 297-302), increased risk of cancer (Wen et al., Cancer Res. 74 (2014) 6589-6597), and heart disease, often the cause of death in these patients (Brittenham, Disorders of iron metabolism: iron deficiency and overload, in: R. Hoffman, E. J. Benz, S. J. Shattil, B. Furie, H. J. Cohen (Eds.), Hematology: Basic Principles and Practice, 3rd Ed., Churchill Livingstone, New York, 2000, pp 397-428). Nontransferrin-bound plasma iron (Brissot et al., Biochim. Biophys. Acta. 2012,1820, (2012) 403-410; Chua et al., Blood 104 (2004, 104,) 1519-1525; Bolli et al., Am. J. Physiol. 259 (1990, 259,) 1901-1911) is the origin of the organ damage that develops with iron overload.
In patients with iron overload disease, the toxicity derives from iron's interaction with reactive oxygen species (Graf et al., “Iron-Catalyzed Hydroxyl Radical Formation. Stringent Requirement for Free Iron Coordination Site.” J. Biol. Chem. 1984, 259, 3620-3624; Halliwell, “Free Radicals and Antioxidants: A Personal View.” Nutr. Rev. 1994, 52, 253-265; Halliwell, “Oxidative Damage, and Chelating Agents.” In The Development of Iron Chelators for Clinical Use; Bergeron et al., Eds.; CRC: Boca Raton, Fla., 1994; pp 33-56; Koppenol, “Kinetics and Mechanism of the Fenton Reaction: Implications for Iron Toxicity.” In Iron Chelators: New Development Strategies; Badman et al., Eds.; Saratoga: Ponte Vedra Beach, Fla., 2000, pp 3-10). For example, in the presence of Fe(II), endogenous H2O2 is reduced to the hydroxyl radical (HO.), a very reactive species, and HO−, in the Fenton reaction. The hydroxyl radical reacts very quickly with a variety of cellular constituents and can initiate free radicals and radical-mediated chain processes that damage DNA and membranes as well as produce carcinogens (Halliwell, “Free Radicals and Antioxidants: A Personal View.” Nutr. Rev. 1994, 52, 253-265); Babbs, “Oxygen Radicals in Ulcerative Colitis.” Free Radical Biol. Med. 1992, 13, 169-181; Hazen et al., “Human Neutrophils Employ the Myeloperoxidase-Hydrogen Peroxide-Chloride System to Oxidize α-Amino Acids to a Family of Reactive Aldehydes. Mechanistic Studies Identifying Labile Intermediates along the Reaction Pathway.” J. Biol. Chem. 1998, 273, 4997-5005). The liberated Fe(III) is reduced back to Fe(II) via a variety of biological reductants (e.g., ascorbate, glutathione), creating a problematic cycle.
Iron-mediated damage can be focal, as in reperfusion damage (Millán et al., “Biological Signatures of Brain Damage Associated with High Serum Ferritin Levels in Patients with Acute Ischemic Stroke and Thrombolytic Treatment.” Dis. Markers 2008, 25, 181-188), Parkinson's (Zecca et al., “Neuromelanin Can Protect Against Iron-Mediated Oxidative Damage in System Modeling Iron Overload of Brain Aging and Parkinson's Disease.” J. Neurochem. 2008, 106, 1866-1875), Friedreich's ataxia (Pietrangelo, “Iron Chelation Beyond Tranfusion Iron Overload.” Am. J. Hematol. 2007, 82, 1142-1146), macular degeneration (Dunaief, “Iron Induced Oxidative Damage as a Potential Factor in Age-Related Macular Degeneration: The Cogan Lecture” Invest. Ophthalmol. Vis. Sci. 2006, 47, 4660-4664), and hemorrhagic stroke (Hua et al., “Long-Term Effects of Experimental Intracerebral Hemorrhage: The Role of Iron.” J. Neurosurg. 2006, 104, 305-312), or global, as in transfusional iron overload, e.g., thalassemia (Pippard, “Iron Overload and Iron Chelation Therapy in Thalassaemia and Sickle Cell Haemoglobinopathies.” Acta. Haematol. 1987, 78, 206-211), sickle cell disease (Pippard, “Iron Overload and Iron Chelation Therapy in Thalassaemia and Sickle Cell Haemoglobinopathies.” Acta. Haematol. 1987, 78, 206-211; Olivieri, “Progression of Iron Overload in Sickle Cell Disease.” Semin. Hematol. 2001, 38, 57-62), and myelodysplasia (Malcovati, “Impact of Transfusion Dependency and Secondary Iron Overload on the Survival of Patients with Myelodysplastic Syndromes.” Leukemia Res. 2007, 31, S2-S6), with multiple organ involvement. The solution in both scenarios is the same: chelate and promote the excretion of excess unmanaged iron.
Treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is the only therapeutic approach available. Some of the iron chelating agents that are now in use or that have been clinically evaluated include desferrioxamine B mesylate (DFO) (Desferal; Novartis Pharmaceuticals Corporation: East Hanover, N.J., 2008; www.pharma.us.novartis.com/product/pi/pdf/desferal.pdf), 1,2-dimethyl-3-hydroxy-4-pyridinone (deferiprone, L1) (Hoffbrand, “Long-Term Trial of Deferiprone in 51 Transfusion-Dependent Iron Overloaded Patients.” Blood 1998, 91, 295-300; Olivieri, “Long-Term Therapy with Deferiprone.” Acta Haematol. 1996, 95, 37-48; Olivieri, “Long-Term Safety and Effectiveness of Iron-Chelation Therapy with Deferiprone from Thalassemia Major.” N. Engl. J. Med. 1998, 339, 417-423; Richardson, “The Controversial Role of Deferiprone in the Treatment of Thalassemia.” J. Lab. Clin. Med. 2001, 137, 324-329), and 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (desferasirox, ICL670A) (Nisbet-Brown et al., “Effectiveness and Safety of ICL670 in Iron-Loaded Patients with Thalassemia: A Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial.” Lancet, 2003, 361, 1597-1602; Galanello et al., “Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to β-Thalassemia.” J. Clin. Pharmacol. 2003, 43, 565-572; Cappellini, “Iron-Chelating Therapy with the New Oral Agent ICL670 (Exjade).” Best Pract. Res. Clin. Haematol. 2005, 18, 289-298). Each of these compounds has shortcomings. DFO must be given subcutaneously (sc) for protracted periods of time, e.g., 12 hours a day, five days a week, a serious patient compliance issue (Olivieri et al., “Iron-Chelating Therapy and the Treatment of Thalassemia.” Blood 1997, 89, 739-761; Pippard, “Desferrioxamine-Induced Iron Excretion in Humans.” Bailliere's Clin. Haematol. 1989, 2, 323-343; Giardina et al., “Chelation Therapy in β-Thalassemia: An Optimistic Update.” Semin. Hematol. 2001, 38, 360-366). Deferiprone, while orally active, simply does not remove enough iron to maintain patients in a negative iron balance (Hoffbrand, “Long-Term Trial of Deferiprone in 51 Transfusion-Dependent Iron Overloaded Patients.” Blood 1998, 91, 295-300; Olivieri, “Long-Term Therapy with Deferiprone.” Acta Haematol. 1996, 95, 37-48; Olivieri, “Long-Term Safety and Effectiveness of Iron-Chelation Therapy with Deferiprone from Thalassemia Major.” N. Engl. J. Med. 1998, 339, 417-423; Richardson, “The Controversial Role of Deferiprone in the Treatment of Thalassemia.” J. Lab. Clin. Med. 2001, 137, 324-329). Desferasirox did not show noninferiority to DFO and is associated with numerous side effects, including some renal toxicity (Nisbet-Brown et al., “Effectiveness and Safety of ICL670 in Iron-Loaded Patients with Thalassemia: A Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial.” Lancet, 2003, 361, 1597-1602; Galanello et al., “Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to β-Thalassemia.” J. Clin. Pharmacol. 2003, 43, 565-572; Cappellini, “Iron-Chelating Therapy with the New Oral Agent ICL670 (Exjade).” Best Pract. Res. Clin. Haematol. 2005, 18, 289-298).
Despite the work on metal chelating agents as described above, there is still a need for other metal chelating agents with more desirable properties (e.g., metal chelating agents with balanced properties (e.g., lipophilicity, metal clearing efficiency, and toxicity)) for better treatment and/or prevention of pathological conditions in a subject.